Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Exposure of dexamethasone-treated cells of the mT-1 line of F111 rat cells bearing a dexamethasone-inducible polyoma virus middle T (mT) antigen gene to very low concentrations of the protein kinase C-stimulating phorbol ester TPA increased the association of mT antigen with the cellular pp60c-src tyrosine protein kinase, as indicated by an increased phosphorylation of tyrosine residues of mT in mT:pp60c-src complexes precipitated from extracts of the TPA-treated cells by anti-mT antibodies. This TPA (hence probably protein kinase C)-enhanced association of mT with pp60c-src was accompanied by a large increase in the transforming ability of mT as indicated by a much enhanced ability of TPA-treated mT-1 cells producing submaximal levels of mT to proliferate while suspended in semi-solid medium and to form foci on confluent monolayers of normal F111 cells. NRCC NO: 26558.
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PMID:Protein kinase C stimulation increases the transforming ability of the polyoma virus middle T antigen. 243 May 71

We have studied the role of guanine-nucleotide binding regulatory proteins (G proteins) in the stimulation of inositol lipid breakdown during mitogenic activation of normal human T lymphocytes. The effect of the mitogen phytohemagglutinin (PHA) was compared with the action of two G-protein activators, fluoroaluminate (AlF4-) and guanosine-5'-O-thiotriphosphate (GTP gamma S). PHA and AlF4- stimulated the breakdown of inositol lipids via both the phospholipase A and C pathways when added to intact lymphocytes. PHA, AlF4- and GTP gamma S also triggered both these pathways when added to permeable lymphocytes. The magnitude of the response obtained with AlF4- and GTP gamma S was about four-fold less than with PHA. This difference was attributable to increases in cAMP elicited by AlF4- and GTP gamma S which inhibited the phospholipase pathways. AlF4-, GTP gamma S, and PHA all stimulated the phosphorylation of a 42 kDa protein on tyrosine residues. We propose a model for the early steps following mitogen binding, including sequential activation of a G protein, phospholipase C, protein kinase C and a tyrosine protein kinase. A parallel pathway involving G protein mediated activation of phospholipase A is also implicated.
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PMID:Evidence that guanine-nucleotide binding regulatory proteins couple cell-surface receptors to the breakdown of inositol-containing lipids during T-lymphocyte mitogenesis. 244 7

Pertussis toxin activates T lymphocytes by a mechanism that is independent of its ADP-ribosylation activity. The toxin stimulates increases in diacylglycerol and intracellular calcium apparently by interacting with a cell surface receptor. Consistent with the production of these second messengers we have found that pertussis toxin activates protein kinase C in the Jurkat cell line. The toxin was also found to activate a tyrosine protein kinase in these cells in a manner similar to that observed with phytohemagglutinin. These results provide evidence that the mechanism of activation of T cells by pertussis toxin involves stimulating the activity of protein kinase C and a tyrosine protein kinase.
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PMID:Pertussis toxin activates protein kinase C and a tyrosine protein kinase in the human T cell line Jurkat. 246 93

The CD4 and CD8 T cell receptor accessory molecules can both be isolated from T lymphocytes in association with p56lck, a membrane-associated, cytoplasmic tyrosine protein kinase that is expressed exclusively in lymphoid cells. The enzymatic activity of p56lck may therefore be regulated by CD4 and CD8 and be important in antigen-induced T cell activation. Exposure of human T cells and some mouse T cells to the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA), an activator of protein kinase C, caused the dissociation of p56lck and CD4. Activation of protein kinase C may therefore interrupt regulation of p56lck by CD4 and alter the ability of p56lck to interact with polypeptide substrates. In contrast, exposure of cells to TPA did not cause dissociation of p56lck and CD8. Regulation of p56lck by CD4 may therefore differ from regulation by CD8.
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PMID:Activators of protein kinase C induce dissociation of CD4, but not CD8, from p56lck. 278 34

Epidermal growth factor (EGF) binds with high affinity and specificity to a single site on the external domain of its transmembrane receptor to activate the tyrosine protein kinase activity of its cytoplasmic portion. The EGF receptor gene is amplified and over-expressed in several human tumors, suggesting that increased concentrations of the proto-oncogene leads to constitutive activity similar to that seen with oncogene erb B. Synthesis and degradation of the EGF receptor are regulated, in addition, covalent modification by phosphorylation regulates activity of the receptor protein. Intramolecular self-phosphorylation of Tyr1173 removes a competitive inhibitory constraint to enhance phosphorylation of substrates. Phosphorylation of Thr654 by protein kinase C decreases high affinity EGF binding and EGF-stimulated tyrosine protein kinase activity, providing a mechanism for heterologous regulation of the EGF receptor by tumor promoters and other ligand X receptor complexes. Extensive regulation contributes to normal growth control, abrogation of regulatory controls contributes to uncontrolled growth as seen with erb B transformation and EGF receptor gene amplification in human tumors.
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PMID:Epidermal growth factor and its receptor. 310 78

The lymphocyte-specific tyrosine protein kinase p56lck is abundantly expressed in L3T4+ (CD4+) and Lyt-2+ (CD8+) T-lymphocytes, where it is predominantly phosphorylated in vivo on the carboxy-terminal tyrosine residue 505 (Y-505). Upon exposure to activating signals (mitogenic lectins, antibodies to the T-cell receptor), the p56lck expressed in normal cloned murine T-cells is modified into a product which migrates at approximately 59 kilodaltons on sodium dodecyl sulfate-polyacrylamide gels and which possesses several amino-terminal serine phosphorylations. The changes in both mobility and amino-terminal phosphorylation can be reproduced by known activators of protein kinase C (4 alpha-phorbol 12 beta-myristate, dioctanoylglycerol), suggesting that this signal transduction pathway (or related pathways) mediates at least part of these events. Interestingly, agents raising intracellular calcium (such as A23187) cause the appearance of several of these amino-terminal phosphorylation changes but do not cause the pronounced shift in electrophoretic mobility. These data suggest that at least two serine kinase systems are implicated in the alterations of p56lck associated with T-cell activation and that the lck gene product plays a critical role in normal T-cell physiology.
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PMID:Alterations of the lymphocyte-specific protein tyrosine kinase (p56lck) during T-cell activation. 314 89

Epidermal growth factor (EGF) and transforming growth factor alpha bind to a common receptor at the cell surface. Both the affinity and the tyrosine protein kinase activity of the receptor are regulated by exogenous factors, such as platelet-derived growth factor. A protein kinase C-dependent (Ca2+/phospholipid-dependent enzyme) and independent regulatory mechanism have been described. The protein kinase C-dependent mechanism results in the inhibition of the affinity and tyrosine kinase activity of the EGF receptor. We describe in this report an alternative mechanism of regulation of the receptor that is mediated by sphingosine. Treatment of WI-38 human fetal lung fibroblasts with 5 microM sphingosine for 2 min at 37 degrees C caused a marked increase in the affinity of the EGF receptor. Similar results were obtained when isolated plasma membranes prepared from these cells were incubated with sphingosine. A stimulation of the EGF receptor tyrosine protein kinase activity was also observed after sphingosine-treatment of plasma membranes. Sphingosine caused a decrease in the Km for ATP and an increase in the Vmax for the tyrosine phosphorylation of a synthetic peptide substrate. Control experiments demonstrated that these actions of sphingosine were not secondary to the inhibition of protein kinase C. These data indicate that sphingosine causes the functional conversion of the EGF receptor into an activated state that expresses both a high affinity for EGF and an increased tyrosine kinase activity. We conclude that sphingosine is a bioactive molecule in human fibroblasts.
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PMID:Two alternative mechanisms control the interconversion of functional states of the epidermal growth factor receptor. 325 97

The role of EGF receptor concentration in tumor growth was investigated in athymic mice by measuring the rate of growth of clonal human epidermoid carcinoma A431 cells containing different extents of EGF receptor gene amplification and protein expression. A direct correlation-between the rate of tumor growth and EFG receptor concentration was found, supporting previous cell culture studies that quantitated the relationship between activated EGF receptors and cell proliferation. Holo EGF receptor is activated by ligand binding to the extracellular domain to activate cytoplasmic tyrosine protein kinase activity. A model of single molecule transmembrane signaling is proposed. The function of two phosphorylation sites on the EGF receptor has been analyzed by use of site-directed mutagenesis. Comparison of normal and mutant hEGF receptors expressed in rodent cells lacking endogenous EGF receptors indicates that: 1) Thr654, located 10 amino acids carboxyl terminal to the inner membrane boundary, is a major site of heterologous regulation via protein kinase C catalyzed phosphorylation, and 2) Tyr1173, the major site of self-phosphorylation, located at the carboxyl terminus, provides a secondary level of regulation of receptor function by acting as a competitive inhibitor with exogenous substrates.
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PMID:Regulatory features of the epidermal growth factor receptor. 331 53

Numerous genes and their products are involved in the expression of the transformed phenotype. Chemical carcinogens transform cells by altering the structure and function of these macromolecules. Some of them have been identified as oncogenes and oncogene products whereas most of the rest are unknown. Since the expressions of transformed phenotype such as alteration of cell morphology, motility and growth are closely correlated to the alteration of cytoskeletal structures, we have investigated the genetic and post-translational alterations of actin and actin-binding proteins in transformed cells. We have found that the expression of a point-mutated beta-actin correlates with the expression of transformed phenotype in one of these chemically transformed human cell lines. Mutated beta-actin showed reduced ability for self-polymerization in vitro, which coincides with the observation in vivo in reduced incorporation of the mutated actin into the cytoskeletal fraction. On the other hand, actin-binding proteins, caldesmon and calspectin which also bind to calmodulin, and 36K protein which also binds to calspectin, were examined using antibodies specific for each protein. Their binding to counterproteins was dependent on the Ca++ concentration. Compared with the untransformed NIH3T3 cells, the NIH3T3 cells transformed by various oncogenes showed considerably smaller amounts of the three proteins and an increase in their phosphorylated forms. The degradation rate of caldesmon and calspectin did not differ between untransformed and transformed cells. Phosphoamino acid analysis showed that the serine residue was the major site for phosphorylation in calspectin whereas calspectin was a good substrate in vitro for both src tyrosine protein kinase and protein kinase C, while 36K protein was phosphorylated at the tyrosine residue as well as the serine residue. The addition of tumor promoter to cultured cells also caused changes in actin-binding proteins simultaneously with changes in morphology, motility and microfilament structure and with the induction of transcription of the beta-actin gene. The role of actin and actin-binding proteins in the cascade reactions induced by oncogene products was discussed.
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PMID:[Malignant transformation and alteration of actin-related proteins]. 360 34

The receptor for epidermal growth factor (EGF) is a 170,000-180,000 molecular weight single-chain glycoprotein of 1,186 amino acids. Its sequence suggests that it has an external EGF-binding domain, formed by the NH2-terminal 621 amino acids, linked to a cytoplasmic region by a single membrane-spanning segment. In the cytoplasmic portion, starting 50 residues from the membrane, there is a 250-residue stretch similar to the catalytic domain of the src gene family of retroviral tyrosine protein kinases, and, indeed, a tyrosine-specific protein kinase activity intrinsic to the receptor is stimulated when EGF is bound. Increased tyrosine phosphorylation of cellular proteins, detected in A431 cells following EGF binding, may be important in the mitogenic signal pathway. Tumour promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA), counteract this increase, as well as causing loss of a high affinity class of EGF binding sites. The major receptor for TPA has been identified as the serine/threonine-specific Ca2+/phospholipid-dependent diacylglycerol-activated protein kinase, protein kinase C. By substituting for diacylglycerol, TPA stimulates protein kinase C. Protein kinase C phosphorylates purified EGF receptor at specific sites, and this reduces EGF-stimulated tyrosine protein kinase activity. TPA treatment of A431 cells increases serine and threonine phosphorylation of the EGF receptor at the same sites, which suggests that the reduction of EGF receptor kinase activity in TPA-treated cells is a consequence of the receptor's phosphorylation by the kinase. We have attempted to identify these phosphorylation sites and show here that protein kinase C phosphorylates threonine 654 in the human EGF receptor. This threonine is in a very basic sequence nine residues from the cytoplasmic face of the plasma membrane in the region before the protein kinase domain; it is thus in a position to modulate signalling between this internal domain and the external EGF-binding domain.
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PMID:Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane. 609 Sep 44


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